OVERALL PROJECT SUMMARY Precision delivery, imaging and therapy of solid tumors (P01) Precision medicine is an approach for disease diagnosis, treatment and prevention that considers individual patient variability in genes, environment, and lifestyle. The aspiration is to use molecular targeted therapies according to `omic' categorization of targeted expression, drug sensitivity and resistance and select a targeted therapy most appropriate for each patient. Most drugs available to implement precision medicine, including chemotherapies and antibodies, require high near-toxic doses only to have small amounts enter solid tumors in patients, and frequently only modest or temporary effects. Delivery may indeed be a universal problem for both tumor imaging and therapy. Delivering drugs precisely into tumors is necessary to maximize therapeutic potency, but is not currently possible. In this era of precision oncology, tremendous progress has been made in the treatment of hematological malignancies; however, for eradicating solid tumors, promising and even existing therapies could be improved significantly with better delivery systems that actively bypass vascular barriers. While targeting strategies have evolved, the long-standing challenge remains of delivering drugs and imaging agents across vascular barriers. Our overall goal is to boost precision drug delivery into solid tumors and lesions by exploiting a highly precise active transvascular transport pathway mediated by the caveolae pumping system. We have identified a tumor- induced target concentrated in specifically in tumor caveolae, and successfully developed the first antibody to penetrate solid tumors actively, rapidly and specifically in preclinical models and deliver attached cargo. We propose here to translate our novel caveolae-targeting strategy into new and enhanced treatments and diagnostic tools for use in human clinical trials. Project 1 will focus on the development of precision antibody imaging agents and radiotherapy of solid tumors for testing in preclinical models. Project 2 will develop novel drug immunoconjugates for clinical testing. Project 3 will evaluate novel caveolae-targeted imaging and therapeutic agents by conducting toxicology studies, a pilot imaging study in human patients to study biodistribution of radiolabeled CTA, and a phase 1 dose escalation study of cisplatin-based CTA conjugates in patients with solid tumors. If successful, this program project will have developed the first precision imaging and therapeutic agents that could radically alter how we treat cancer and metastatic disease.